Prediction of Chameleonic Efficiency

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Ų was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R²=0.92) with an experimental measure of hydrogen bond donor potential, Δlog P_oct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.     

Macroscopic and Microscopic Structures of Cesium Lead Iodide Perovskite from Atomistic Simulations

A first‐principles‐based effective Hamiltonian is developed and employed to investigate finite‐temperature structural properties of a prototype of perovskite halides, that is CsPbI₃. Such simulations, when using first‐principles‐extracted coefficients, successfully reproduce the existence of an orthorhombic Pnma state and its iodine octahedral tilting angles around room temperature. However, they also yield a direct transformation from Pnma to cubic $Pm\overline{3}m$ upon heating, unlike measurements that reported the occurrence of an intermediate long‐range‐tilted tetragonal P4/mbm phase in‐between the orthorhombic and cubic phases. Such disagreement, which may cast some doubts about the extent to which first‐principle methods can be trusted to mimic hybrid perovskites, can be resolved by “only” changing one short‐range tilting parameter in the whole set of effective Hamiltonian coefficients. In such a case, some reasonable values of this specific parameter result in the predictions that i) the intermediate P4/mbm state originates from fluctuations over many different tilted states; and ii) the cubic $Pm\overline{3}m$ phase is highly locally distorted and develops strong transverse antiphase correlation between first‐nearest neighbor iodine octahedral tiltings, before undergoing a phase transition to P4/mbm under cooling.     

Primary (granulomatous) angiitis of the central nervous system with multiple aneurysms of spinal arteries. Case report

A 55-year-old woman with primary (granulomatous) angiitis of the central nervous system in association with non-Hodgkin's lymphoma (mucosa-associated lymphoid tissue type) presented with an acute spinal subdural hemorrhage secondary to rupture of one of several fusiform inflammatory aneurysms of the spinal cord radicular arteries. The literature on hemorrhagic complications, aneurysms, and spinal cord involvement in granulomatous angiitis is reviewed. Recognition of granulomatous angiitis is important, as the condition may be responsive to immunosuppressive therapy.     

Induction of mosaic sex-linked recessive lethals in the different germ cell stages of Drosophila melanogaster by bleomycin

The dead-end filtration characteristics of the dimorphic yeast Kluyveromyces marxianus var. marxianus (formerly fragilis) NRRLy2415 were investigated for a range of mean cell morphologies, ranging from predominantly yeast-like to predominantly filamentous. Semiautomated image analysis was used to measure the mean cell specific surface area, Sv, and the mean ratio of cell length to equivalent cylindrical diameter, Ldm, in each broth. The method of Ju and Ho (Biotechnol. Bioeng. 1988, 32, 95-99) was used to show that for broths with Ldm values between 1.72 and 10.03, the voidage of cell pellets formed by centrifugation increased with increasing Ldm. In the pressure range 30-180 kPa, the specific filter cake resistance, alpha, was found to be related to pressure, DeltaP, through the equation alpha = alpha0(1 + kcDeltaP). The dependence of alpha0/Sv2 on Ldm was found to be qualitatively consistent with the pellet voidage data and the Carman-Kozeny equation. Considerably better agreement with the experimental data was obtained when the Kozeny constant, K, was treated as variable and related to Ldm through the equation K = 4.83 + 7.08 log10 Ldm. The cake compressibility constant, kc, was found to increase with increasing Ldm, a phenomenon consistent with the wide range of voidages that can be displayed by beds of long cylinders.     

High brachial artery bifurcation: a report of 2 cases

High division of the brachial artery was observed in two cadavers, during routine dissection of upper extremities. In the first case, the brachial artery of the right upper extremity was divided into its two terminal branches immediately after passing between the lateral and medial roots of the median nerve and just below the origin of the profunda brachii artery. The lateral branch was the radial artery, located in the space normally occupied by the brachial artery and the medial one was the ulnar artery. In the second case, the brachial artery was divided into its two terminal branches just below the origin of the profunda brachii artery. Accurate knowledge of the relationships and course of these major arterial conduits and particularly of their variational patterns, is of considerable practical importance in the conduct of reperative surgery in the arm, forearm and hand.     

Assay of oral vaccination of dogs against rabies in Tunisia with the vaccinal strain SADBern

The possibility of immunizing dogs orally against rabies, using SADBern, an attenuated strain, was tested on dogs in the field in Tunisia. This strain induced high neutralizing antibody titres and conferred to all vaccinated dogs total resistance against a challenge with a Maghrebian strain. However, an excretion of virus of vaccinal origin was observed in one dog, hampering the use of SADBern in dogs. Nevertheless, this work demonstrates for the first time that dogs in developing countries, especially those which are inaccessible to parenteral vaccination, could be efficiently immunized against rabies by the oral route.     

Microsatellite markers in leukaemia and lymphoma: comments on a timely topic

Microsatellites are unique highly polymorphic and informative genetic markers dispersed in the human genome. Their detection by PCR is rapid and a wide variety of DNA sources including archival material are available for diagnostic purposes. Microsatellite typing of haematological neoplasms may be applied to the search for loss of heterozygosity at loci possibly harbouring tumour suppressor genes, for example in acute lymphoblastic leukaemia. The technique may detect submicroscopical chromosomal deletions which are not visible in the leukaemic karyotype. RER+ tumours exhibiting microsatellite instability appear to be rare among haematological cancers with the possible exception of lymphoid tumours in immunosuppressed patients and lymphomas derived from mucosa-associated lymphoid tissue. An X-chromosomal microsatellite near the human androgen receptor gene (HUMARA) may be used for clonal X-inactivation analysis. Microsatellites therefore represent a collection of powerful genetic markers suitable to tackle questions relevant to basic research and clinical problems in leukaemia and lymphoma.     

Cure of malignant ascites and generation of protective immunity by monoclonal antibody-targeted activation of a glucuronide prodrug in rats

We examined the in vivo efficacy of targeting beta-glucuronidase (betaG) to activate a glucuronide prodrug (BHAMG) of p-hydroxyaniline mustard (pHAM) at hepatoma ascites in Sprague-Dawley rats. Injection i.p. of 500 microg RH1-betaG, a conjugate formed between recombinant betaG and monoclonal antibody RH1 with specificity for an antigen expressed on AS-30D rat hepatoma cells, into rats bearing AS-30D ascites resulted in the accumulation of 54 microg conjugate per 10(9) tumor cells after 2 hr. Ascites fluid and serum contained 0.53 and 0 microg/ml, respectively, RH1-betaG 2 hr after injection of the conjugate. Conjugate binding to AS-30D cells was heterogeneous and non-saturated, as determined by flow cytometry. BHAMG was less toxic than pHAM to SD rats based on measures of animal mortality, weight loss and hematological toxicity. Treatment of rats bearing established hepatoma ascites with 500 microg RH1-betaG followed 2 hr later with a single i.p. injection of 30 mg/kg BHAMG or 3 i.p. injections of 10 mg/kg BHAMG 2, 3 and 4 hr later resulted in the cure of 6/8 and 8/8 animals, respectively. Treatment with BHAMG or pHAM alone did not produce cures, whereas treatment with a control antibody-betaG conjugate and BHAMG produced significantly greater hematological toxicity compared to treatment with RH1-betaG and BHAMG. All cured rats were completely protected from rechallenge with 2 x 10(7) AS-30D cells, indicating that successful treatment of animals induced protective immunity.     

Hepatotoxin (microcystin) and neurotoxin (anatoxin-a) contained in natural blooms and strains of cyanobacteria from Japanese freshwaters

Amounts of hepatotoxic microcystin and neurotoxic anatoxin-a were estimated in natural blooms and strains of cyanobacteria from freshwaters in Japan. A simultaneous analysis method of anatoxin-a and microcystin was applied to natural bloom samples, which has been dominated by several species and the strains of cyanobacteria which produced simultaneously both toxins. The natural blooms examined in the present study were mainly composed of Anabaena and Oscillatoria, but most also contained Microcystis and other cyanobacteria. Only one sample was almost unialgal, Anabaena spiroides, collected from Lake Sagami. The toxins in 14 samples collected from nine different natural blooms during 1988-1992 were identified as microcystins-RR, -YR, and -LR; desmethyl-7-microcystin-LR (7-DMLR); and anatoxin-a. Microcystins were the main toxins contained in these natural blooms, with anatoxin-a not being detected or of very little quantity. 7-DMLR was detected in samples only from Lake Kasumigaura. Five strains of Anabaena isolated from waters in Japan produced a small amount of anatoxin-a, but no microcystins. One half of the strains of Microcystis produced microcystins and/or anatoxin-a. This is the first study showing Microcystis producing both anatoxin-a and microcystins.